HYPOTHYROID AND AUTONOMIC CHANGES--ROLE OF MEDULLARY TRH

甲状腺功能减退症和自主神经变化——髓质 TRH 的作用

• 批准号: 2749564
• 负责人: HONG YANG
• 金额: $ 8.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-10 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2749564
• 关键词: albino rat; autonomic nervous system; blood pressure; dorsal motor nucleus; efferent nerve; gastrins; gastrointestinal motility /pressure; gene expression; heart rate; hormone receptor; hormone regulation /control mechanism; hypothyroidism; in situ hybridization; medulla oblongata; neuroendocrine system; neurotransmitter transport; northern blottings; receptor expression; serotonin; serotonin receptor; somatostatin; thyroid hormones; thyroidectomy; thyrotropin releasing hormone; vagus nerve

The central mechanisms responsible for the bradycardia, high blood pressure, gastrointestinal motility disorder, and gastric atrophy induced by hypothyroidism remains unknown. Recent studies revealed that TRH and serotonin (5-HT), synthesized and co-existing in medullary raphe nuclei and innervating spinal sympathetic and medullary vagal preganglionic motoneurons, play important roles in central autonomic regulation. The hypothesis of the present proposal is that thyroid hormone modulates the autonomic nervous system by influencing the synthesis and functions of TRH and 5-HT located in the medullary raphe nuclei. The specific aims are: (1) to evaluate whether medullary TRH and 5-HT are involved in the autonomic disorders in hypothyroidism. The vagal efferent discharges, heart rate and blood pressure, gastric and intestinal motility, antral gastrin and somatostatin gene expression will be measured in eu- and hypothyroid rats. Intracisternal or intrathecal injections and microinjection into the medullary vagal motonuclei (DMN and Amb) of TRH and 5-HT or TRH antibody and specific 5-HT receptor antagonists will be performed to imitate or to reverse the autonomic disorders observed in the hypothyroidism. (2) to demonstrate that thyroid hormones regulate TRH gene expression and 5-HT turnover as well as c-fos expression in the medullary raphe nuclei. TRH mRNA levels by Northern blot analysis and in situ hybridization, 5-HT turnover by HPLC and c-fos expression by immunohistology will be measured under conditions of thyroid activity. The time courses will be observed and the plasma thyroid hormone levels will be correlated with these changes. (3) to study the distribution and regulation of thyroid hormone receptors in the medullary raphe nuclei. A polymerase chain reaction based assay will be used to characterize alpha and beta thyroid hormone receptor mRNA expression in rat medulla. In situ hybridization will be used to locate the receptor gene expression under different conditions of thyroid activity. The proposed studies will provide evidence that thyroid hormone may act directly on the medullary nuclei related to autonomic function by regulating the synthesis and turnover of its neuropeptides and neurotransmitters and will yield substantive information on the mechanisms through which autonomic disorders participate in the clinical manifestations of thyroid diseases.

导致心动过缓、高血脂的中枢机制 压力、胃肠动力障碍、胃萎缩等 甲状腺功能减退症引起的目前尚不清楚。最近的研究表明 TRH 和 血清素 (5-HT)，合成并共存于中缝髓核中 和支配脊髓交感神经和髓质迷走神经节前 运动神经元在中枢自主神经调节中发挥重要作用。 本提案的假设是甲状腺激素调节 通过影响自主神经系统的合成和功能 TRH和5-HT位于髓中缝核。具体目标是： (1)评价髓质TRH和5-HT是否参与 甲状腺功能减退症中的自主神经紊乱。迷走神经传出神经放电， 心率和血压、胃和肠蠕动、胃窦 胃泌素和生长抑素基因表达将在欧盟和 甲状腺功能减退大鼠。脑池内或鞘内注射和 TRH 的髓质迷走神经运动核（DMN 和 Amb）显微注射 5-HT或TRH抗体和特异性5-HT受体拮抗剂将 进行模仿或逆转在观察到的自主神经紊乱 甲状腺功能减退症。 (2)证明甲状腺激素调节TRH基因 髓质中的表达和 5-HT 周转以及 c-fos 表达 中缝核。通过 Northern 印迹分析和原位检测 TRH mRNA 水平 杂交、通过 HPLC 检测 5-HT 周转以及通过检测 c-fos 表达 免疫组织学将在甲状腺活性的条件下进行测量。这 将观察时间进程并且血浆甲状腺激素水平将 与这些变化相关。 (3) 研究分布 中缝髓核中甲状腺激素受体的调节。一个 基于聚合酶链反应的测定将用于表征 α 和β甲状腺激素受体mRNA在大鼠髓质中的表达。原位 杂交将用于定位受体基因表达 甲状腺活性的不同条件。 拟议的研究将提供甲状腺激素可能起作用的证据 直接作用于与自主神经功能相关的髓核 调节其神经肽的合成和周转 神经递质并将产生有关机制的实质性信息 自主神经紊乱通过其参与临床 甲状腺疾病的表现。